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Chemosensitization by a Non-apoptogenic Heat Shock Protein 70-Binding Apoptosis-Inducing Factor Mutant

¹ Institut National de la Santé et de la Recherché Médicale U-517, Faculty of Medicine and Pharmacy, Dijon, France;
² Centre National de la Recherché Scientifique UMR 1599, Institute Gustave Roussy, Villejuif, France;
³ Department of Chemistry, Queen Mary-University of London, London, United Kingdom;
⁴ Molecular Modeling and Design, Pharmacia, Nerviano, Italy;
⁵ Apoptosis Laboratory, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark;
⁶ Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada;
⁷ Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri;
⁸ Reproductive Toxicology Division (MD-72), National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina; and
⁹ Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom

Heat shock protein 70 (HSP70) inhibits apoptosis and thereby increases the survival of cells exposed to a wide range of lethal stimuli. HSP70 has also been shown to increase the tumorigenicity of cancer cells in rodent models. The protective function of this chaperone involves interaction and neutralization of the caspase activator apoptotic protease activation factor-1 and the mitochondrial flavoprotein apoptosis-inducing factor (AIF). In this work, we determined by deletional mutagenesis that a domain of AIF comprised between amino acids 150 and 228 is engaged in a molecular interaction with the substrate-binding domain of HSP70. Computer calculations favored this conclusion. On the basis of this information, we constructed an AIF-derived protein, which is cytosolic, noncytotoxic, yet maintains its capacity to interact with HSP70. This protein, designated ADD70, sensitized different human cancer cells to apoptosis induced by a variety of death stimuli by its capacity to interact with HSP70 and therefore to sequester HSP70. Thus, its chemosensitizing effect was lost in cells in which inducible HSP70 genes had been deleted. These data delineate a novel strategy for the selective neutralization of HSP70.

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